Patch system for monitoring and enhancing sleep and circadian rhythm alignment

ABSTRACT

Disclosed are novel compositions, devices, patches, systems and methods that are useful for estimating, determining, modulating and/or improving the sleep/wake and/or circadian phase of a subject (e.g., a human subject) by the dispensing of measured quantities of agents to a subject or into an environment of the subject and the continuous monitoring and/or tracking of the subject&#39;s consciousness (e.g., sleep/wake) patterns. In certain aspects, the compositions, devices, patches, systems and methods disclosed herein are capable of delivering one or more agents to a subject in response to measured consciousness patterns estimations and circadian phase estimations, thereby aligning the subject&#39;s circadian biology to the external environment and improving the quality and duration of sleep.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of co-pending U.S. application Ser.No. 16/258,472, filed Jan. 25, 2019 which claims priority to, and thebenefit of, U.S. Provisional Application No. 62/621,898, filed Jan. 25,2018, and U.S. Provisional Application No. 62/692,292, filed Jun. 29,2018. The disclosures of said provisional applications are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present inventions relate to the field of devices and systems formeasuring, tracking, and actuating on sleep/wake and circadian rhythmsvia direct and indirect stimuli, including delivering certain agentsand/or conditioned olfactory stimuli at specific times of day andspecific times relative to scheduled sleep/sleep states to improve sleepand facilitate sleep hygiene.

BACKGROUND OF THE INVENTION

Circadian rhythms are endogenous biological rhythms that have a periodof about twenty-four hours that allow the brains and bodies of a subject(e.g., a mammal) to anticipate and prepare for daily events (e.g.,waking up, eating, sleeping). Circadian rhythms persist in the absenceof external cues (e.g., solar light/dark cycle) and are entrainable(e.g., can be reset by exposure to stimuli, such as light). Circadianrhythms are displayed in the biology, physiology, and behaviors of mostorganisms on earth, including humans. For example, circadian rhythmsfavor sleep at certain times of day and wake at others and alsoinfluence a host of other physiologic and behavioral processes includingalertness, performance, hormone production, metabolism, drug metabolism,cardiovascular functioning, etc. A functional circadian system is vitalfor optimal health, performance, and survival.

Core body temperature and dim light melatonin onset (DLMO) are commonlyused markers for monitoring internal circadian phase or biological time(e.g., what time it is in the brain) in humans. In addition, monitoringsleep/wake patterns across days and weeks allows for theprediction/estimation of circadian phase. When internal circadian timeis aligned to the external environment, physiological and behavioralprocesses are enhanced (e.g., enhanced or improved sleep, cognitive andphysical performance, alertness, metabolism, and gastrointestinalfunction); however, when the internal circadian timing system andexternal environment are misaligned (e.g., due to shiftwork or jetlag) ahost of physiological and behavioral processes are negatively impacted.

Several stimuli have direct and indirect influence on circadian rhythms,sleep, and performance (e.g., light and melatonin) and the appropriatelytimed (e.g., circadian phase, time relative to sleep or wake, and timerelative to scheduled performance) administration of such stimuli, forexample, can shift circadian biology to better match the externalenvironment thereby enhancing performance, alertness, mood, sleep, etc.of a subject. The appropriately timed delivery of these stimuli isparamount. The administration of circadian-targeted stimuli (e.g., lightand melatonin) can have an undesired outcome (e.g., decreasedperformance, alertness and/or disrupted sleep) if administered at theincorrect time/phase.

Needed are new strategies, devices and methods for estimating ordetermining the circadian phase of a subject (e.g., a human subject).Also needed are new strategies, devices and methods of delivering to asubject certain sleep, circadian and/or performance enhancing stimuli toenhance sleep and/or align circadian biology to an external environment(e.g., the subject's present environment or an anticipated environment).Insufficient sleep and sleep disruption negatively impact awake timefunctioning, quality of life, and both physical and mental health.Improving one's sleep is critical for professionals who operate inadverse environments, such as military personnel, astronauts, truckdrivers, night shift employees, and individuals stationed in noise proneenvironments. Improving one's sleep becomes particularly difficult whenit depends on improving the sleep of another person first orenvironmental factors out of their control (noise, light, etc.). Forexample, military personnel (e.g., during combat) and new parentsexperience significant disruption to sleep quality and amount, as wellas parents of children with autism or other children with special needs.One of the major issues in pediatric populations, as well as some adultpopulations, is a lack of non-pharmaceutical based sleep aids that aresafe to use in newborns or in children with autism who are already onother medications, for example. Thus, also needed are minimallyinvasive, safe and effective systems to improve sleep in populationswhile being capable of acquiring feedback and performing adjustment andcustomization for different subjects and changing environments oractivity patterns.

SUMMARY OF THE INVENTION

Disclosed herein are novel compositions, devices, systems and methodsuseful for estimating and/or determining the circadian phase of asubject by the continuous monitoring and/or tracking of consciousnesspatterns (e.g., sleep/wake patterns) of the subject. The consciousnesspatterns (comprising sleep and/or wake pattern data) monitoring andcircadian phase estimations are used to appropriately determine and timethe delivery of sleep, circadian, and performance agents. Sleep,circadian, and performance agents may include or comprise, for example,stimulants, such as caffeine, performance enhancing stimuli, such as,for example, steroids, sleep inducing agents, such as sedatives (e.g.,sleeping pills) or phase shifting medications/stimuli, such as melatoninor light. Delivery of such agents (e.g., circadian agents) at theappropriate time(s) serve to align the subject's circadian biology tothe external environment. The result of aligning the subject's circadianbiology with the external environment is the enhancement of thesubject's physiological and cognitive processes.

Certain embodiments disclosed herein are directed to devices, patchesand systems for determining, estimating, monitoring and/or tracking oneor more of activity patterns, inactivity patterns, polysomnographicpatterns and circadian states of a subject. Additionally, the devices,patches or systems include or comprise a microcontroller, volatile andnon-volatile memory, a communications interface, and a battery, one ormore electrical pads configured to contact skin of the subject andcollect and monitor polysomnographic data for the subject, one or moreactuating devices configured for controlled transdermal delivery of oneor more agents that alter circadian rhythm, sleep and/or alertness stateof the subject through at least one nozzle, and a container encasing themicrocontroller, the volatile and non-volatile memory, thecommunications interface, the battery, the one or more electrical pads,the one or more actuating devices, and the at least one nozzle.

In some embodiments, such devices, patches and systems further includeor comprise a flexible circuit board with the microcontroller, thevolatile and non-volatile memory, the communications interface, thebattery, the one or more electrical pads, and the one or more actuatingdevices embedded thereon. In some aspects, the flexible circuit board iscoated with impermeable resin or other material to prevent damage frommoisture. In some embodiments, monitoring polysomnographic datacomprises measuring polysomnographic data selected from the groupconsisting of brainwave data, eye movement data and muscle tone data,collected from one or more patch mounted sensors, andactivity/inactivity patterns are monitored by one or more sensorsmeasuring rest and activity cycles via actigraphy. In some aspects, theone or more electrical pads are further configured to measure at leastone of skin temperature and blood oxygen saturation levels of thesubject. In still other embodiments, the one or more electrical pads arefurther configured to sense pulse/blood oximetry and analyze sweat andother skin secretions of the subject.

In certain embodiments, the devices, patches and systems disclosedherein are configured to be worn on the skin of a subject, and thecontainer further includes a breathable polymer or fabric that allowsthe skin of the subject to breathe while maintaining close contact withthe skin of the subject. In certain aspects, such polymer or fabric mayalso act as an occlusive material to facilitate the transdermalabsorption of one or more agents. In some aspects, the container furtherincludes a skin-compatible adhesive to adhere the patch to skin of thesubject. In still other embodiments, the container further includes aconductive gel or adhesive to increase conductivity of skin of thesubject and the one or more electrical pads.

In certain aspects, the devices, patches and systems disclosed hereininclude or comprise a communications interface configured to communicatewith other patches, and/or transfer measured and calculated data to bestored at or by other patches containing memory, and/or trigger thedelivery of stimuli in other patches that are capable of delivering suchstimuli. For example, such a communications interface may communicatewith the other patches by applying low power electrical signals to theskin of the subject such that the signals propagate on the surface ofthe skin to the other patches.

In certain aspects, the container of the devices, patches and systemsdisclosed herein further include or comprise a vessel capable of storingvarious doses of an agent to be delivered transdermally to the subjectby the one or more actuating devices. Similarly, in other aspects thedevices, patches or systems disclosed herein further include or comprisephotodiodes configured to measure environmental light exposure, and forestimating the total light dosage (e.g., stimulus content) received bythe subject over a period of time, wherein a specific time relative tosleep onset, offset, or estimated circadian phase at which the lightstimuli were received can also be derived from these measurements.

The devices, patches and systems disclosed herein may be configured todeliver one or more agents, for example, one or more agents selectedfrom the group consisting of a central nervous system depressant and acentral nervous system stimulator. In certain aspects, the one or moreagents modulate the circadian biology of the subject. In certainaspects, the one or more agents include or comprise one or more centralnervous system depressants (e.g., a central nervous system depressantselected from the group consisting of an opioid, a hypnotic, abenzodiazepine, a barbiturate, a sleeping medication, a pain medication,and combinations thereof). In certain aspects, the one or more agentsinclude or comprise one or more phase shifting medications/stimuli,(e.g., melatonin or light). In certain aspects, the one or more agentsinclude or comprise one or more central nervous system stimulants (e.g.,a central nervous system stimulants selected from the group consistingof light, caffeine, modafinil, methylphenidate and combinationsthereof). In some embodiments, the one or more agents include orcomprise combinations of one or more central nervous system depressants,one or more phase shifting stimuli, and one or more central nervoussystem stimulants.

Also disclosed herein are methods and systems of modulating thecircadian phase of a subject in response to the subject's environment,such methods and systems comprising steps of: initializing a wearableskin-patch positioned on skin of a subject, the patch comprising amicrocontroller, a volatile and non-volatile memory, a communicationsinterface, a battery, one or more electrical pads, one or more actuatingdevices, and at least one nozzle, collecting and monitoringsleep/wake/polysomnographic data, by the one or more electrical pads, ofthe subject, estimating or determining, by the microcontroller, acircadian phase of the subject based on the collected and monitoredactivity/inactivity patterns polysomnographic data, and delivering oneor more agents, through at least one nozzle in controlled transdermaldelivery, by the one or more actuating devices, to the skin of thesubject based on the estimated or determined circadian phase, whereinthe delivery of the one or more agents modulate the circadian phase ofthe subject in response to the subject's environment. Delivery of theone or more agents may be provided at a specific time relative tosleep/wake based on collected or historical data or during a specificsleep state (e.g., relying upon sensor input and data, such as frompolysomnography) or delivery of the one or more agents may be providedat a specific circadian phase (e.g., based upon monitored sleep/wakepatterns).

In certain aspects of the foregoing methods and systems, the one or moreagents are selected from the group consisting of one or more centralnervous system depressants and one or more central nervous systemstimulants. In certain aspects of the foregoing methods and systems, theone or more agents include or comprise one or more central nervoussystem depressants (e.g., one or more central nervous system depressantsselected from the group consisting of an opioid, a hypnotic, abenzodiazepine, melatonin and combinations thereof). In certainembodiments, the one or more agents include or comprise one or morecentral nervous system stimulants (e.g., light, caffeine, modafinil,methylphenidate and combinations thereof).

In certain aspects of the foregoing methods, the agent is or comprisesan olfactory agent. Olfactory agents comprise non-invasive, effectivenon-pharmaceutical based sleep, wake, energy and/or relaxation enhancersthat are safe to use in humans including vulnerable populations (e.g.,newborns, children with autism, and/or those who are already on othermedications). The result of enhancing sleep, enhancing alertness,aligning the subject's circadian biology with the external environmentis a system that improves sleep in populations that cannot or prefer notto use pharmaceutical interventions, shifting of timing of sleep,adjusting circadian phase, enhancing alertness, enhancing performance,reducing sleep onset latency, enhancing sleep consolidation and reducingvariability in sleep patterns, adjusting mood and enhancingphysiological processes. For example, olfactory agents can beautomatically dispensed at specific times of day or specific timesrelative to sleep/wake to facilitate at least one action selected fromthe group consisting of sleep, wake, increased energy, and relaxation.Delivery of such agents sets a sleep-and-wake schedule for the subjectand, in certain embodiments, specific olfactory agents may bespecifically assigned to activity events selected from the groupconsisting of bed time, rise time, nap time, awake time and combinationsthereof. In certain aspects, the systems and inventions disclosed hereinuse algorithms to avoid habituation to agents (e.g., olfactory agents)relative to onset of activity events.

In certain aspects of the devices, patches, systems and methodsdisclosed herein, the subject is a mammal, more specifically a humansubject (e.g., an adult, an elderly adult, an adolescent or an infant).

Certain example embodiments of the present invention disclosed hereinare directed to a system for adjusting consciousness patterns(comprising sleep and/or wake pattern data) and circadian states of oneor more subjects. For example, in certain aspects the system includes anolfactory dispensing unit configured to dispense olfactory agents, acontrol unit, a user interface and a set of sensors. The control unitconfigured to actuate the olfactory dispensing unit and store data fromone or more sensors configured to perform one or more functions selectedfrom the group consisting of estimating and tracking activity andinactivity data for the one or more subjects, measuring a presence thenconcentration of olfactory agents, collecting and monitoringconsciousness patterns data for the one or more subjects, andquantifying measurements of circadian outcomes for the one or moresubjects. The user interface receives control commands, input from auser (e.g., the subject), for using the control unit to actuate theolfactory dispensing unit to dispense the olfactory agents. Theolfactory dispensing unit and the control unit are configured to be inelectronic communication, and the user interface and the control unitare configured to be in electronic communication. The system dispensesthe olfactory agents to modulate a circadian phase and consciousnessstate of the one or more subjects in response to a condition of the oneor more subjects and an environment of the one or more subjects.

In accordance with aspects of the present invention, the olfactorydispensing unit can be one or more containers that store the olfactoryagents, and one or more actuators that dispense the olfactory agentsinto the environment of the one or more subjects.

In certain aspects of the present invention, the control unit canactuate the olfactory dispensing unit as a function of time, accordingto a formulation, using a timing device configured to keep time. Thecontrol unit can use memory to store the olfactory formulation and datafrom the one or more sensors and other system components, using aprocessor to compute relevant parameters and adjust the formulation inreal-time to control timing indicating when olfactory agents aredispensed and amounts indicating how much olfactory agents are dispensed(e.g., indicating the volume of olfactory agents dispensed). Theolfactory dispensing unit can be configured to dispense olfactory agentsusing an actuator that uses at least one mechanism selected from thegroup consisting of electrical heating of olfactory agents comprisingone or more liquids actuated by the control unit at specific timesdesignated by the formulation to cause evaporation, ultrasonicnebulizers comprising a vibrating transducer actuated by the controlunit, one or more solids in contact with a heating element actuated bythe control unit at specific times designated by the formulation tofacilitate delivery of olfactory agents, ultrasonic nebulizerscomprising a vibrating transducer actuated by the control unit,air-stream atomizers comprising an air-stream generator actuated by thecontrol unit, and volatile substances stored in a container that isopened and closed by the control unit to allow and prevent vapors of theolfactory agents to propagate out of the olfactory dispensing unit intothe environment of the one or more subjects.

In certain aspects of the present invention, the olfactory agents canmodulate sleep, alertness, and/or circadian biology of the one or moresubjects.

In certain aspects of the present invention, the one or more sensors canbe configured to perform collecting and monitoring of consciousnesspatterns data for the one or more subjects. The monitoring ofconsciousness patterns data can include or comprise using the sensors toquantify the sleep and circadian patterns of the one or more subjects bysensing at least one signal, which at least one signal may be selectedfrom the group consisting of rest and activity cycles using actigraphy,signals using polysomnography, skin temperature, sleep onset time andduration, environmental light exposure, total light dosage received bythe one or more subjects over a period of time, pulse oximetry, bloodoxygen saturation levels, sweat and other skin secretions of the one ormore subjects, and biofeedback signals indicative of sleep patterns ofthe one or more subjects.

In certain aspects of the present invention, the control unit canreference, use or otherwise rely on consciousness pattern data of eachof the one more subjects to optimize a formulation of the olfactoryagents in real-time to provide cues to achieve a stimuli response ineach of the one or more subjects. The stimuli response can be one ormore actions selected from the group consisting of shifting of timing ofsleep, adjusting circadian phase, enhancing alertness, enhancingperformance, reducing sleep onset latency, enhancing sleep consolidationand reducing variability in sleep patterns and adjusting mood.

In certain aspects of the present invention, the system can include orcomprise at least one smart olfactory dispensing unit and software thattracks sleep history information of the one or more subjects, then setsa sleep-and-wake schedule for the one or more subjects and designatesspecific olfactory agents assigned to activity events selected from thegroup consisting of bedtime, risetime, nap time, awake time andcombinations thereof. The olfactory agents can be automaticallydispensed at specific times of day to facilitate at least one actionselected from the group consisting of sleep, wake, increased energy, andrelaxation. The system uses algorithms to avoid habituation to olfactoryagents relative to onset of activity events.

In certain aspects of the present invention, the one or more sensors canbe configured to sense the environment of the one or more subjects bydirectly measuring the concentration of olfactory agents in the air ofthe environment of the one or more subjects, allowing the system tocontrol a quantity of olfactory agents present in the environment of theone or more subjects. The one or more sensors can include or comprise asensor selected from the group consisting of sensors configured forestimating concentrations in air for certain specific gases, sensorsconfigured for estimating concentrations in air for volatile organiccompounds, sensors that map aromas to images and combinations thereof.

In certain aspects of the present invention, a formulation can includeor comprise a list of times and desired concentrations of the olfactoryagents at each time. The concentrations of olfactory agents for use inthe formulation can be determined from measured amounts of the olfactoryagents absorbed by the one or more subjects over a certain exposureperiod. The concentrations of olfactory agents for use in theformulation can be measured using absolute units, empirical units andcombinations thereof.

In certain aspects of the present invention, the control unit canactuate the olfactory dispensing unit to dispense olfactory agents withoutput and intensity based upon measurements of circadian outcomes andapplication of machine learning techniques to indirectly infer adequateconcentrations of a formulation and the olfactory agents in anenvironment of the one or more subjects.

In certain aspects of the present invention, the olfactory dispensingunit and the control unit both can be contained within a physical devicethat further comprises a smart plug and wireless communication unit, andwherein a formulation is stored in memory of the control unitcontrolling dispensing of the olfactory agents. The control unit can becontrolled remotely using wireless electronic communication sent from aseparate device comprising the user interface configured to receiveinput from the user (e.g., a subject) to modify parameters of the systemand adjust the formulations.

In certain aspects of the present invention, the control unit can bephysically separated from the olfactory dispensing unit and communicateselectronically with the olfactory dispensing unit using wired orwireless technologies. The control unit can use processors, memory anddedicated software that control the system and the control unit isphysically connected to the user interface configured to receive inputfrom the user (e.g., a subject) to modify parameters of the system andadjust the formulations.

In certain aspects of the present invention, the control unit, theolfactory dispensing unit and the one or more sensors can communicateelectronically using transceivers, wireless communication units andwireless routers configured to operate using wireless technologystandards selected from the group consisting of Bluetooth®, Bluetooth®low energy (BLE), Zigbee®, Wi-Fi®, infrared, near field communicationand combinations thereof.

In certain aspects of the present invention, the system can include orcomprise a fan, configured to circulate air through the system.

In certain aspects of the present invention, the olfactory agents caninclude or comprise one or more agents that can be central nervoussystem depressants or central nervous system stimulators.

In certain aspects of the systems and methods disclosed herein, thesubjects are mammals (e.g., humans).

In certain aspects of the present invention, one or more sensors caninclude or comprise a skin-compatible adhesive to adhere the one or moresensors to skin of the one or more subjects.

Also disclosed herein are devices, systems and methods of modulating andadjusting consciousness patterns and circadian states of one or moresubjects in response to the subjects' environment, such devices, systemsand methods comprising steps of: providing an olfactory dispensing unit;actuating the olfactory dispensing unit using a control unit, andstoring data from one or more sensors; performing, using the one or moresensors, a function selected from the group consisting of estimating andtracking activity and inactivity data for one or more subjects,collecting and monitoring consciousness patterns data for one or moresubjects, and quantifying measurements of circadian outcomes for one ormore subjects; inputting, using a user interface, control commands forusing the control unit to actuate the olfactory dispensing unit todispense the olfactory agents; electronically communicating, between theolfactory dispensing unit and the control unit and between the userinterface and control unit; and dispensing of the olfactory agents,thereby modulating sleep/wake and/or a circadian phase of the one ormore subjects in response to a condition of the one or more subjects andan environment of the one or more subjects.

In certain aspects of the foregoing devices, systems and methods, theone or more sensors are configured to collect and monitor consciousnesspatterns data of the one or more subjects. The monitoring consciousnesspatterns data can comprise using the one or more sensors to quantify thesleep and circadian phase/rhythms of the one or more subjects by sensingat least one signal selected from the group consisting of rest andactivity cycles using actigraphy, signals using polysomnography, skintemperature, sleep onset time and duration, environmental lightexposure, total light dosage received by the one or more subjects over aperiod of time, pulse oximetry, blood oxygen saturation levels, sweatand other skin secretions of the one or more subjects, and biofeedbacksignals indicative of sleep patterns of the one or more subjects. Thecontrol unit can use consciousness patterns data of each of the one moresubjects to optimize a formulation of the olfactory agents in real-timeto provide cues to achieve a stimuli response in each of the one or moresubjects. The stimuli response can include or comprise one or moreactions selected from the group consisting of shifting of timing ofsleep, reducing sleep onset latency, enhancing sleep consolidation andreducing variability in sleep patterns.

In certain aspects of the foregoing devices, systems and methods, thecontrol unit can actuate the olfactory dispensing unit as a function oftime, according to a formulation, using a timing device configured tokeep time. The control unit can use memory to store the formulation anddata from the one or more sensors and other system components, using aprocessor to compute relevant parameters and adjust the formulation inreal-time to control timing when the olfactory agents are dispensed andamounts indicating a quantity of the olfactory agents to dispense. Theolfactory dispensing unit can be configured to dispense the olfactoryagents using an actuator that uses at least one mechanism selected fromthe group consisting of electrical heating of olfactory agentscomprising one or more liquids actuated by the control unit at specifictimes designated by the formulation to cause evaporation, ultrasonicnebulizers comprising a vibrating transducer actuated by the controlunit, air-stream atomizers comprising an air-stream generator actuatedby the control unit, and volatile substances stored in a container thatis opened and closed by the control unit to respectively allow andprevent vapors of the olfactory agents to propagate out of the olfactorydispensing unit and into the environment of the one or more subjects.

The above discussed, and many other features and attendant advantages ofthe present inventions will become better understood by reference to thefollowing detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 depicts a side/cross section view of the device.

FIG. 2 illustrates a bottom view of the patch, showing a (set of)contact(s) (yellow) for measuring electrical signals on the skin, aswell as the nozzles for the substance dispenser.

FIG. 3 illustrates a top view of the patch (ambient side). Thetransparent outward facing window allows for the measurement of lightlevels (lux) and color/spectral composition.

FIG. 4 illustrates commonly used positions for EEG electrodes, withpreferred measurement points in the present inventions indicated byshading.

FIG. 5 depicts an outline (dashed curve) and electrode locations (redX's) for a patch that measures Fp1, Fp2, and FpZ on the forehead.

FIG. 6 depicts an outline and electrode locations for a patch thatmeasures signals on the subject's forehead at locations Fp1, Fp2, andFpZ, as well as the subject's eye movement.

FIG. 7 illustrates an outline and electrode locations for a patch thatmeasures a subject's chin muscle movements.

FIG. 8 illustrates activity data collected with a prototype activitymeasuring patch device placed on the subject's collar bone region incomparison with data collected with a wrist actigraph.

FIG. 9 illustrates sleep/wake estimates computed from data generated bythe activity measuring patch device in comparison with the sameestimates computed from the wrist actigraph's data.

FIG. 10 illustrates one activity data record as produced by the activitymeasuring patch device spanning approximately 850 1-minute epochs.

FIG. 11 illustrates an overview of the components and data flow of thesystem.

FIG. 12 illustrates the flow of data and electronic communication forused components for embodiments of the system.

FIG. 13 illustrates an embodiment where the system is configured to usewireless electronic communication.

FIG. 14 illustrates an embodiment of the system wherein the control unitand olfactory dispensing unit operate within a single device.

FIG. 15 depicts an embodiment of the system wherein the control unit anddispensing unit operate as a smart plug.

FIG. 16 depicts an illustrative flowchart showing the method forcarrying out the operation of the system.

DETAILED DESCRIPTION OF THE INVENTION

An illustrative embodiment of the present invention relates tocompositions, devices, systems and methods for adjusting (e.g.,advancing, delaying, stabilizing, etc.) consciousness patterns(comprising sleep and/or wake pattern data) and circadian states of oneor more subjects. In certain embodiments, the subject inventions aredirected to wearable skin-patches and related systems for determiningand/or estimating and tracking a subject's sleep/wake patterns andcircadian state, as well as for administering timed agents (e.g.,stimuli) with the object of shifting and/or aligning the subject'scircadian state to external schedules based on measured data and smartalgorithms. In certain aspects, the patches and systems disclosed hereininclude or comprise patches that are worn on the skin of a subject. Incertain embodiments, the patches and systems described herein comprise,include or comprise or are equipped with one or more different sensorsand actuator devices, a microcontroller, volatile and non-volatilememory for storing program code and measured data, a communicationsinterface, wired or wireless, that allows for data to be transferredfrom the patches to a computer, tablet or phone, a real-time clock forproviding timestamps for the measurements, and a battery, which can berechargeable or not. In certain embodiments, the system uses a controlunit to control a dispensing unit to dispense olfactory agents inspecific quantities over specific time durations together with sensorsthat provide data about the subjects and environment for estimating andtracking subject activity (e.g., sleep/wake), collecting and monitoringconsciousness patterns of subjects and quantifying circadian outcomes ofsubjects, wherein the system comprises a user interface for users toinput commands to the control unit, which is in electronic communicationwith the components of the system to modulate a circadian phase andconsciousness state or consciousness pattern (comprising sleep and/orwake pattern data) of the one or more subjects by dispensing quantitiesof the olfactory agents over time in response to a condition of the oneor more subjects and an environment of the one or more subjects. Thenovel compositions, devices, systems and methods are useful forestimating and/or determining the circadian phase of a subject by thecontinuous monitoring and/or tracking consciousness patterns of asubject. These sleep/wake pattern monitoring and circadian phaseestimations are used to appropriately determine and time the delivery ofolfactory agents for promoting sleep, circadian phase, and performance.In certain embodiments, the agents may comprise one or more sleep,circadian, and performance agents, for example, stimulants, such ascaffeine, performance enhancing stimuli, such as, for example, steroids,sleep inducing agents, such as sedatives (e.g., sleeping pills) or phaseshifting medications/stimuli, such as melatonin or light. Delivery ofsuch agents (e.g., olfactory agents) at the appropriate time aligns thesubject's circadian biology to the external environment. The result ofdirectly enhancing sleep/wake and/or aligning the subject's circadianbiology with the external environment is the enhancement ofphysiological and cognitive processes. Unlike other systems that employdrugs to adjust consciousness patterns, this system accomplishesadjusting consciousness patterns (comprising sleep/wake pattern data)and circadian states of one or more subjects using safer olfactoryagents.

In certain embodiments, patches with different functions include orcomprise the devices, systems and methods of modulating and adjustingconsciousness patterns and circadian states of one or more subjects inresponse to the subjects' environment disclosed herein. In certainaspects of the foregoing patch devices, systems and methods, one or moresensors are configured to perform these different functions to collectand monitor consciousness patterns data of the one or more subjects. Insome embodiments, these functions include or comprise monitoring asubject's rest and activity cycles via actigraphy (movement measurementwith an accelerometer), measuring environmental light exposure withphotodiodes or other light sensitive devices, collecting and monitoringpolysomnographic data (e.g., electroencephalogram, electrooculogram, andelectromyogram, and electrocardiogram) via electrical pads that contactthe subject's skin, measuring the subject's skin temperature, and/ormeasuring the subject's blood oxygen saturation levels. In certainaspects, the patch systems disclosed herein also allow for timed (e.g.,both time of day, time relative to sleep, and/or circadian phase)transdermal delivery of one or more agents (e.g., natural substances)that alter or otherwise modulate circadian rhythm (e.g., agents such ascaffeine and melatonin), as well as for transdermal sensing, such aspulse/blood oximetry and analysis of sweat and other skin secretions ofthe subject (e.g., for hormones or metabolites that may containinformation relevant for the assessment and manipulation of circadianrhythms and sleep patterns). The monitoring consciousness patterns datacan include or comprise using the one or more sensors to quantify thesleep and circadian system of the one or more subjects by sensing atleast one signal selected from the group consisting of rest and activitycycles using actigraphy, signals using polysomnography, skintemperature, sleep onset time and duration, environmental lightexposure, total light dosage received by the one or more subjects over aperiod of time, pulse oximetry, blood oxygen saturation levels, sweatand other skin secretions of the one or more subjects, and biofeedbacksignals indicative of sleep patterns of the one or more subjects. Thesystem can use consciousness patterns data of each of the one moresubjects to optimize manipulation of circadian rhythms and sleeppatterns in real-time to provide cues to achieve a stimuli response ineach of the one or more subjects. The stimuli response can include orcomprise one or more actions selected from the group consisting ofshifting of timing of sleep, reducing sleep onset latency, enhancingsleep consolidation, reducing variability in sleep patterns, reducingfatigue and increasing alertness and focus. The internal memory of thepatch possess the capability to download a tapered dosage plan to beimplemented at controlled intervals using intervention schedulers ratherthan simply receiving a signal from sensors/external sources at theappropriate interval to administer the appropriate dosage based onmeasured response. Additionally the patch/device can contain programlogic to derive intervention schedules without having to communicate toan external computer. An array of one or more patches may also becontrolled by the means of communication via one or more externalcomputers (including one or more central computers) to initiate oradjust delivery of agents in an integrated and coordinated manner.

In some embodiments, the patch includes a flexible circuit board with amicrocontroller, memory (for program and data storage), real-time clock,sensors, battery, antenna, and a means of communicating with andtransfer data to the external world, which could be wired (e.g., USB,UART, CAN, SPI, I2C, etc.) or wireless (e.g., Bluetooth, BLE, RF,Zigbee, WiFi, RFID, etc.). In certain embodiments, the circuitcomponents may be coated with impermeable resin or other material toprevent damage from moisture.

In certain embodiments, an envelope or pouch container comprising ormade at least partially of a breathable polymer or fabric, or othermaterial that allows the subject's skin to breathe while maintainingclose contact with the subject's skin is used to house and protect thecircuit board. In certain embodiments, a skin-compatible adhesiveattaches the device to the skin of a subject.

In certain embodiments, for certain applications the devices, systemsand methods disclosed herein may include or comprise a conductive gel oradhesive for increasing the conductivity of the subject's skin whenmeasuring electrical signals generated by the subject's brain, eyes,muscles, or the heart.

In certain aspects, the device, systems and methods disclosed hereininclude or comprise one or more sensing electrodes, terminals and/orprobes on the device-skin interface and that may be used to allowmeasurements to be conducted onto the subject's skin surface. In certainembodiments, the devices, systems and methods disclosed herein (e.g., apatch) may communicate with other patches either wirelessly or via verythin wires. For wireless communication both short (e.g., RFID) and longrange (e.g., BLE, WiFi and/or Zigbee) technologies may be used.Alternatively, low power electrical signals of certain frequenciesapplied to the skin and propagate on the surface of the subject's skinmay be used by patches to communicate with other patches (e.g., otherpatches worn by the subject).

In one preferred embodiment, the patch includes or is equipped withsensors to measure actigraphy and/or response time. In such embodiments,the sensors may include or comprise an accelerometer for measuring asubject's movement, and a thermometer, for measuring the subject's skinsurface temperature. In certain aspects, the devices (e.g., a patch)disclosed herein may include or comprise one or more or an LED,pushbutton or capacitive touch sense pad for measurement of a subject'sreaction times (e.g., modified psychomotor vigilance task).Alternatively, in certain aspects the pushbutton/pad may be substitutedby detection of finger tapping motion via the accelerometer. The one ormore sensors may be physically or electrically connected in a variety ofconfigurations known to persons of ordinary skill in the art. In certainaspects, sensors may be part of the patch as a component of the samephysical package, wherein the sensors connect to the patchmicrocontroller via wires or physical placement on the same circuitboard. In this configuration the sensors receive power from the samepower pack that powers the patch (comprising a battery, etc.). Incertain other aspects one or more sensors may be external (not connectedto the patch) or stand-alone components, connected to the system or thepatch via one of the wireless protocols described herein or known topersons of ordinary skill in the art. In this configuration sensors willbe equipped with sensor-specific batteries or power supplies. Moregenerally, sensor networking may be achieved via any one of variousnetwork topologies known to persons of ordinary skill in the art,including but not limited to: point to point, mesh, star, etc. Sensornetworking depends on how the intervention scheduler is configured. Ifthe scheduler runs on a central node/computer that processes theinformation gathered from various sensor nodes and then sends outcommands/schedules to various devices, then a type of star topology ispreferred. If, on the other hand, the schedule computation is done inthe device itself, then a mesh or ring topology is preferred. In thislatter case very small amounts of data are transferred between devices,mostly for the devices to check their schedule computations against theother devices and computers. Sensor data storage requirements also varybased on implementation. Where the patch is to compute sleep sleep/wakeon the fly based on sensor data, store the minute by minute sleep statesfor the past few days, and then use that information to computeintervention schedules on the fly, small amounts of memory are required.This type of implementation is feasible as long as the algorithms forcomputing sleep state and deriving schedules are no too complex, andwill only require the memory available within the microcontroller one.g., a circuit board. If the algorithms are complex, then the patch'smicrocontroller will likely not have enough computational power toexecute the algorithms. In this case a network solution is required,where the patch transmits sensor data to one or more central computers,which then perform the computations and returns the interventionschedules to the patches. In either embodiment, the patch controllercomprises a built in real time clock that keeps track of time fortimestamping sensor measurements, timing delivery of agents comprisingdosages, etc. Each patch may perform data analysis and provide feedback,including intervention schedules and delivery of one or more agents, ina variety of ways including: using only the patch's microcontroller,using an array of patches and associated data, using a networked set ofone or more central computers, and combinations thereof, where sensordata from the various sources may be integrated (using e.g., the meansof communication detailed herein) to perform such tasks.

In another preferred embodiment, the patch design may include orcomprise a transparent, outside facing window, through which certainenvironmental conditions, such as light levels (Lux), light dosage, andlight color and/or light spectral information can be measured. Incertain aspects, these measurements are collected usingphotometer/photodiode chips, on-chip filter colorimeters, reverse biasedcolor LEDs, or on-chip spectrometers.

In another embodiment, the compositions and systems (e.g., a patch)disclosed herein contains electrodes that contact the subject's skin andhouse analog amplifiers that condition PSG signals measured on thesurface of the subject's skin or scalp before they are processed andstored by the microcontroller. Various such electrode-containing patchesmay be attached to various points on the subject's body to capturespecific signals relevant to PSG.

In certain embodiments, the compositions and systems (e.g., a patch)disclosed herein include or comprise a container capable of storingvarious doses of an agent (e.g., a central nervous system stimulant ordepressant) known to influence or modulate a subject's sleep, circadianrhythms, and or performance, such as caffeine or melatonin, to bedelivered transdermally in a timed manner, as determined by algorithmscontained in the system and by parameters derived from previouslycollected data. For instance, activity counts may be collected by thesubject patches and systems using an accelerometer and scored as sleepor wake in 1-minute intervals. Form these sleep/wake timing data,circadian phase and timing of biological day/night can be estimated.These estimates of biological day and night will be interpreted incombination with the desired timing of performance. One example of howalgorithms are generated includes the knowledge of an individualsubject's (or group of subjects') current location (e.g., Boston),location of destination (e.g., London, UK), and the amount of time untilarrival at destination. In the current, example, London is 5 hours aheadof Boston, the subject's biological clock needs to be advanced (movedforward in time) in order for performance to be enhanced while inLondon. Thus, in such embodiments the patch and systems disclosed hereinwould administer melatonin the phase advance region of the melatonin andlight in the phase advance portion of the phase response curve.

In certain aspects, the container is actuated via an electrical signalfrom the microcontroller to perform timed delivery of the agent onto theskin of the subject. Because certain agents such as caffeine andmelatonin can be absorbed by the skin of a subject and do not need to bedriven into the skin (e.g., via iontophoresis), in certain aspects thecompositions and system described herein operate by delivering (e.g.,spraying) a predetermined dose of caffeine onto the subject's skin andallowing the sprayed content to be absorbed by the skin.

Referring to FIG. 1 , the circuitry of the patch is laid out on aflexible sheet material [1], such as pyralux, that allows the patch toconform to the contour of the region of the subject's body to which itis applied. In some embodiments, particularly where the circuitry can becontained in small device areas, a conventional hard printed circuitboard may be used. Circuit components [2] are soldered to the copper,tin or silver tracks [3] on the pyralux or on the hard circuit boardwith lead-free solder. Electrical components and tracks may be placed onboth sides of the pyralux sheet and the sides may be electricallyconnected with vias [4]. The circuitry may then be covered with a thinimpermeable layer of acrylic or silicone polymer, or the entire deviceis placed in a sealed plastic or polymer envelope to protect the circuitelements from moisture and other environmental elements that could causedamage. Alternatively, the circuit and tracks may be printed withsilver-based ink onto a thin and flexible film, such as polyethyleneterephthalate (PET). The layer is then covered in acrylic or silicone tobecome impermeable to moisture.

On top of the flexible circuit board a protective sheet [5] may be usedthat can be made of woven fabric, plastic (PVC, polyethylene orpolyurethane), or latex. The edges of the adhesive sheet extend beyondthe edges of the circuit board. This sheet forms the outward facing sideof the device, and serves to conceal and protect the device circuitry,as well as to provide a free adhesive border to attach the device to theskin. One or more transparent windows [6] may be fabricated onto thisprotective sheet, by cutting a hole on the sheet and then covering thehole with transparent flexible film material, such as polyethyleneterephthalate (PET). Such windows allow light from the externalenvironment to be captured by sensors placed on the printed circuitboard.

On the bottom side of the flexible printed circuit board is a permeablefabric [7], such as cotton cloth or polyester, that may be used to allowthe skin to breath and to absorb sweat. The edges [8] of the permeablefabric [7] are glued to the protective sheet [5] with a high tackadhesive to form a sealed pocket [9] that houses the circuit board [1].Alternatively, the circuit board [1] is glued directly to the protectivesheet [5] with high tack adhesive, and a bottom layer is not used, inwhich case the bottom of the circuit board [1] makes direct contact withthe skin of a subject.

One or more contacts may be attached on the permeable fabricbottom-layer [7] to allow measurement of electrical signals on the skinof a subject, such as for PSG applications. The contact pads are made ofconductive material. In one example, the conductive pad is made of apiece of metal-clad pyralux or a thin, flexible copper film, coated witha thin layer of gold for passivation, and glued on the edges so as tocover a hole cut on the fabric bottom layer [7]. In another example, thecontact pads may be directly woven into the fabric bottom layer [7] withconductive yarn. Electrical contact to the contact pads is extended fromthe printed circuit board with wires, vias, or solder.

Adhesive [11], compatible with the skin of the subject (e.g., a humansubject), is applied to the bottom of the device, either (preferably)only on the edges of the protective sheet [5] that are exposed (e.g.,not covered by the permeable fabric bottom-layer [7]), or, in caseswhere the permeable fabric bottom-layer [7] is not used, on the entirebottom surface of the device.

In some applications, the bottom surface of the device, including thecontact pads [10], that is not covered by adhesive may be coated with aconductive electrolyte solution/gel or other conductive substance toallow measurement of electrical signals on the skin.

For transdermal delivery of agents, such as caffeine and/or melatonin,the devices and/or patches disclosed herein may house a container forstoring such agents in either liquid/gel/foam form. A mechanism foractuating the container with electrical pulses may be used to controlthe delivery of the agents onto or into the skin of the subject. Incertain embodiments, the mechanism for actuating the substance containerconsists of a piezo-actuated nozzle or set of nozzles [13], similar tothose found on the cartridges of some inkjet printers, such as thoseproduced by EPSON. Some other types of inkjet printers rely on atemperature actuated mechanism for dispensing a liquid agent, whichinvolves heating the liquid to high temperatures and forming steam. Incertain aspects, the selected temperature to which such agents areheated take into consideration whether the agents may be heat-labile(e.g., heating certain agents such as caffeine or melatonin solutions toproduce steam that may degrade or alter the stability or efficacy ofsuch agents).

In certain aspects, the nozzles are positioned on the bottom face of thepatch, preferably so that their exit surface stays slightly above theskin surface. When actuated a certain number of times by electricalpulses produced by the microcontroller, the nozzles spray a dose of thesubstance onto the skin of the subject. The precise dose amount iscontrolled via 1) the number of nozzles, 2) the rate at which thenozzle(s) dispense(s) the agent (e.g., a liquid agent) with eachelectrical pulse, 3) the number of pulses applied, 4) the dilution andcomposition of the agents loaded into the patches, and 5) the rate andefficiency with which the skin absorbs the agents.

For measurement of electrical signals, particularlyelectroencephalographic or electrooculographic, electrodes are placed ondifferent positions on the subject's head (scalp). One preferredpositioning of the electrodes is indicated in FIG. 4 , which shows thecommon locations for electrodes using the International 10-20 EEGplacement system (Jasper, H. H. (1958). The ten-twenty electrode systemof the International Federation. Electroencephalography and ClinicalNeurophysiology, 10, 371-375, the entire contents of which areincorporated by reference herein). In certain embodiments, not all ofthe electrode locations will be used by the present compositions andsystems for determining sleep/wake state. In certain aspects, theelectrodes of the present compositions and systems will include orcomprise includes Fp1[15], Fp2 [16], Fz and reference electrodes FpZ[14], A1 and A2. Fp=Frontal pole, which is 10% from the nasion, based onthe distance from nasion to inion. Fp1 and Fp2 are each 5% distance tothe left (Fp1) or right (Fp2) Fp, based on the distance frompre-aricular to pre-aricular.

In some subject, the location Fz may be obstructed by hair. In certainembodiments, such as that depicted in FIG. 5 , at least three electrodesare used—one of these being an active electrode located at Fp1 [15],another being an active electrode located at Fp2 and the third being areference electrode located at Fpz [14]. The colored/shaded region inFIG. 5 indicates a possible form for such a patch. The electroniccomponents are not shown in the FIG. 5 , and the electrode locations areindicated with an X.

In some embodiments, the patches and devices disclosed herein can extendaround the eyes of a subject to include or comprise electrodes and forcapturing such subject's eye movements, as depicted in FIG. 6 . In someembodiments, the subject's eye movement is detected by electrodespositioned on the outer canthi and placed slightly above or below themidline of the subject's pupil—and [19], as illustrated in FIG. 6 .Because these electrodes have to be referenced to the same voltageground level, they must be electrically connected via physical conductorwires to the other electrodes to which they are referenced. This meansthat the patches and devices used in this type of measurement mustextend and connect all of the involved electrodes, rather thancomprising physically (and electrically) isolated patches.

In another preferred embodiment, electrodes positioned on the chin, asindicated in FIG. 7 , are used to measure muscle movement.

In one embodiment, the subject inventions include or comprise one ormore patches that can be deployed in a military population (e.g., ARMY,NAVY, AIR FORCE, etc.) to track a subject's sleep duration andfrequency, and to estimate the subject's circadian phase and administerone or more agents (e.g., stimulants or sedatives or sleep/circadianstimuli) in order to prepare the subject for mission critical work.

In some aspects, the subject inventions include or comprise one or morepatches can be deployed in a medical setting on subject for whomchronotherapy would reduce the side effects of certain medications orwhere administration of medication is more desirable during sleep (e.g.,sleeping pill) or during a particular state of sleep (e.g., hormones).

In some aspects, the subject inventions include or comprise one or morepatches that can be deployed in space on astronaut subjects in a similarcapacity to that in military personal. Patches can be deployed inpediatric populations that have been historically difficult to study dueto available technology to track sleep (e.g., babies or children withautism).

In some embodiments, the subject inventions include or comprise one ormore patches that can be deployed in any individual subject whomperforming well at various circadian phase and various intervals of timeawake is important (e.g., businessmen, professional athletes, Olympicathletes, shift workers, medical professionals, pilots, captains, truckdrivers, emergency responders, etc.).

In any of the foregoing embodiments, data measured by the variousfunctions described and included in the patch devices disclosed hereinallow for measurement and estimation of the crucial parameters thatinfluence the subject's circadian rhythm, namely, sleep onset time,sleep frequency, sleep duration, quality of sleep (presence ofdisturbances/wake events, etc.). Knowledge of sleep parameters allowsfor the programmed delivery of stimuli aimed at regulating sleep,improving sleep conditions, shifting sleep onset times according todesired schedules (e.g., time zone changes, etc.), and stabilizing sleepschedules in relation to activities for achieving peak cognitive and/orphysical performance and disposition.

FIG. 8 depicts data collected by deployment of a patch and system 100wherein data were collected during a 28-hours forced desynchronylaboratory study (FD).

Activity/inactivity raw data from patch sensors across seven earth daysare presented. The graph at the top shows activity level on the y-axisand earth day on the x-axis. A clear pattern of high activity (wake) andlow activity (sleep) are seen across study days. The smaller graphs showsleep/wake estimates based from the raw data in the top graph.Actigpatch sleep/wake estimates (left), Ambulatory Monitoring, Inc.(AMI) actigraphy sleep/wake estimates (right) and the comparison ofActigpatch to AMI estimates (bottom) are displayed. These figuresconfirm high reliability in sleep/wake estimates between Actigpatch andAMI devices.

FIG. 9 depicts data collected during a one night in-laboratory studymeasuring polysomnography (PSG) and activity/inactivity using theActigpatch. Patch-based sleep/wake estimates across one night arepresented in the top graph. The subsequent graphs showpolysomnographically (PSG) measured sleep/wake scored according toRechtschaffen and Kales (1968) criteria (top) and Actigpatch vs. PSGsleep/wake (bottom). These data show reliability in sleep/wake estimatesbetween Actigpatch and PSG.

FIG. 10 depicts data collected by Actigpatch showing activity level(y-axis) across 24 hours (1 minute epochs; x-axis). Circadian phase wasmeasured from salivary dim light melatonin onset (DLMO). A predictabletime interval occurs between DLMO and sleep onset and this figuredemonstrates that DLMO (circadian phase) can be estimated from sleepestimates derived from patch data collected from a subject.

FIGS. 11 through 16 illustrate an example embodiment or embodiments ofthe devices, systems and methods for estimating, modulating andimproving the circadian phase and consciousness patterns of a subject(e.g., a human subject) by the dispensing of measured quantities ofolfactory agents into an environment of the subject and the continuousmonitoring and/or tracking of the subject's consciousness patterns,thereby aligning the subject's circadian biology to an externalenvironment, improving the quality and duration of sleep, according tothe present invention. Although the present invention will be describedwith reference to the example embodiment or embodiments illustrated inthe figures, it should be understood that many alternative forms canembody the present invention. One of skill in the art will additionallyappreciate different ways to alter the parameters of the embodiment(s)disclosed, such as the size, shape, or type of elements or materials, ina manner still in keeping with the spirit and scope of the presentinvention.

FIG. 11 depicts an overview of the components and data flow of thesystem 100. An aspect of the invention provides a system 100 foradjusting consciousness patterns/sleep/wake patterns and circadianstates of one or more subjects 118 based on tracking and estimatingsubject 118 responses, the system comprising a control unit 104 tocontrol an olfactory dispensing unit 102 and being operative to dispenseolfactory agents 120 including at least one of: a fragrance, odor,scent, and olfactory stimuli, which are dispensed during a programmed orspecified time/circadian phase relative to sleep onset/offset in orderto facilitate, enhance, and consolidate sleep or enhance mood andalertness in a subject. In certain embodiments, the subject 118 is ahuman (e.g., a shift worker or a member of the military), but may beanother organism that has suitably responsive olfactory cells.

In general, the control unit 104 applies an olfactory formulation tofacilitate or enhance sleep or the timing of sleep or enhancealertness/performance and mood. The control unit 104 controls a set ofolfactory agents 120 including at least one of odors, scents, fragrancesand olfactory stimuli to set a prescribed olfactory supplement and/orschedule. In an embodiment of the system 100, the control unit 104,olfactory dispensing unit 102 and the olfactory agents 120 are assembledin a kit or container, which is portable.

The control unit 104 in various embodiments receives a biofeedbacksignal or data indicative of one or more subjects' 118 consciousnesspatterns, defined as either sleep patterns, patterns detected from asubject 118 while awake, or a combination of both, and determines theformulation in accordance with that signal or data, to achieve a desiredresponse in the subject 118 (e.g., shifting of the subject's timing ofsleep, reducing sleep onset latency, enhancing sleep consolidation,reducing variability in sleep patterns, etc.). The control unit 104 ofthe system 100 allows for timed (e.g., both time of day, time relativeto sleep, and/or circadian phase) delivery of precisely measuredquantities of olfactory agents 120 that alter or otherwise modulatecircadian rhythms and consciousness patterns of subjects 118, whereinthe control unit 104 comprises a real-time clock or timing device forproviding precise times to perform functions and timestamps for themeasurements taken by the system 100.

This system 100 is located in a designated area (e.g., bedroom,bathroom, playroom, office, car, gym, plane, ship, etc.) defined as theenvironment 101 of the one or more subjects 118.

The method of olfactory agent 120 delivery is not crucial for theoperation of the system 100, however, ability to control the timing(when) and amounts (how much) of olfactory agent 120 delivery is centralto the system's 100 operation. FIG. 12 illustrates the flow of data andelectronic communication for commonly used components for embodiments ofthe system. The olfactory agent 120 delivery can be accomplished via theuse of electrical heating of odor oils and other liquids to causeevaporation (a similar operative mechanism to commercial scented oilheating devices e.g., Glade® Plug-Ins®), via ultrasonic nebulizers, viaair-stream atomizers, or via the use of volatile substances. In the caseof electrical heating, the heater must be actuated by the control unit104 at specific times dictated by the formulations; for the ultrasonicnebulizer, the vibrating (piezo) element must be actuated by the controlunit 104; for the air stream nebulizers, an air pump or other air-streamgenerating device must be actuated by the control unit 104; for volatilesubstances, the compartment containing the substance must be opened andclosed by the control unit 104, allowing or not allowing the vapors topropagate out of the device and into the air. A fan (not shown), forcirculating air through the device or the system 100 may be added.

Each olfactory formulation consists of a list of times and desiredolfactory stimulus (odor, aroma) concentrations, in the form ofolfactory agents 120, at each time. The critical quantity that dictatesthe system's 100 operation and quantifies the size of the olfactorystimulus is the amount of olfactory agents 120 absorbed by the subject118 over a certain period (i.e. concentration multiplied by exposuretime). Insofar as the formulation is concerned, the stimulus andolfactory agent 120 concentrations can be measured in absolute units(e.g., μg of odor per liter of air) or in “empirical” units (e.g., theconcentration that results when the olfactory dispensing unit 102 isactuated for X units of time in a room of Y cubic meters of volume).Once the characteristics of the dispenser are known, these twomeasurement methods are completely equivalent.

The control unit 104 actuates the olfactory dispensing unit 102 as afunction of time, according to the formulation. The control unitcontains a clock that allows it to keep time for precise functioninitiation and timestamping data, and memory 108 (comprising volatileand non-volatile memory for storing program code and measured data) tostore the formulation. Additionally, the control unit's 104 memory 108may store data from sensors 114 and other devices that allow it tocompute relevant parameters and adjust the formulation in real-time. Thecontrol unit uses consciousness patterns data of each of the one moresubjects to optimize a formulation of the olfactory agents in real-timeto provide cues to achieve a stimuli response in each of the one or moresubjects. Optimization occurs when the measured stimuli response of theone or more subjects matches the data provided by the formulation anduser input including maintaining specific concentrations of olfactoryagents in the environment 101 and absorbed by the one or more subjects118. The stimuli response comprises one or more actions selected fromthe group consisting of shifting of timing of sleep, adjusting circadianphase, enhancing alertness, enhancing performance, reducing sleep onsetlatency, enhancing sleep consolidation and reducing variability in sleeppatterns and adjusting mood. When internal circadian time is aligned tothe external environment, physiological and behavioral processes areenhanced (e.g., sleep, cognitive and physical performance, alertness,metabolism, and gastrointestinal function perform more efficiently).Alertness and performance are defined and measured by comparison ofpatterns of activity for persons awake with historic activity withrespect to timing to perform known tasks and accuracy in performance.Enhancing sleep consolidation means reducing in duration or removingdiscontinuities in sleep or lengthening the duration of uninterruptedsleep or both. Adjusting mood means delivering olfactory agents 120known to cause physiological changes to observed phenomena identified inthe art as moods or triggering behavior in a subject usingpre-conditioning of the subject to initiate or cease moods based onprior associations and administrations of olfactory agents 120. Severalstimuli have direct and indirect influence on circadian rhythms, sleep,and performance (e.g., light, melatonin and caffeine) and theappropriately timed (e.g., circadian phase, time relative to sleep orwake, and time relative to scheduled performance) administration of suchstimuli, for example, can shift circadian biology to better match theexternal environment, thereby enhancing performance, alertness, mood,sleep, etc. of a subject. Different formulations that promote differentstimuli responses may be stored in the memory 108 of the control unit,input by the user, or determined by analysis of sensor 114 dataprocessed by the processor 106 of the control unit 104. The control unit104 works in conjunction with a user interface 116 that may be acomponent of the control unit 104 or a separate component, wherein theusers can modify the system's 110 parameters, tweak formulations, etc.This user interface 116 can be provided via wired (USB, UART, etc.) orwireless technologies (Bluetooth, Bluetooth low energy (BLE), Zigbee,Wi-Fi, infrared, near field communication, etc.) or via a display andbuttons on the control unit 104 itself. The control unit 104 can be adedicated hardware device, built solely for the purpose of controllingthis system 100, or a general purpose device, such as a smart-phone or atablet computer running dedicated software that controls the system. Thesystem 100 can include or comprise software that tracks sleep historyinformation of the one or more subjects, then sets a sleep-and-wakeschedule for the one or more subjects and designates specific olfactoryagents assigned to activity events selected from the group consisting ofbedtime, risetime, nap time, awake time and combinations thereof. Theolfactory agents can be automatically dispensed at specific times of dayto facilitate at least one action selected from the group consisting ofsleep, wake, increased alertness, and relaxation. The system usesalgorithms to avoid habituation to olfactory agents relative to onset ofactivity events. In addition to the control unit 104, the system 100comprises sensors 114, and the olfactory dispensing unit 102, whichcomprises one or more containers 122 that store the olfactory agents120, and actuators 124 that deliver the olfactory agents 120 into theenvironment 101. Different system embodiments can be contemplated.Various methods of actuation are possible.

The system 100 may comprise one or more sensors 114, that collect dataand measurements associated with the subject 118, the environment 101 ofthe subject 118, or both. In some cases, it may be possible to directlymeasure the concentration of olfactory stimulant or olfactory agents 120in the air. Technologies for measuring aromas are a subject of currentactive development. Sensors 114 for certain specific gases and volatileorganic compounds (VOC) may be suitable for estimating the concentrationof certain aromas in the air. Certain novel sensors 114 that map aromasto images (e.g., the Aroma Bit sensor) may be suitable for theseapplications. In such cases when aroma concentrations can be measured orestimated directly, the system 100 can be operated as a “servo” toprecisely control the quantity of olfactory agent 120 present in the airat any given time. If measurement of such concentration is not possible,then the system 100 operates exclusively as an actuator, and its output(or intensity) must be configured according to the ambient environment101 in which it is used for achieving the desired concentrations.Additionally, if such direct measurements of the olfactory agent's 120concentration are impossible, the system's 100 operation may also beprecisely controlled as a “servo” by measurements of circadian outcomesand application of machine learning techniques to indirectly inferadequate concentrations. In certain embodiments, the functions of theone or more sensors 114 quantify the subject's 120 sleep and circadiansystem including monitoring a subject's rest and activity cycles viaactigraphy (movement measurement with an accelerometer), recordingmovements and activity, measuring environmental light exposure withphotodiodes or other light sensitive devices, collecting and monitoringpolysomnographic data (e.g., electroencephalogram, electrooculogram, andelectromyogram, and electrocardiogram) via electrical pads that contactthe subject's skin, measuring the subject's skin temperature, measuringthe subject's blood oxygen saturation levels, transdermal sensing, suchas pulse/blood oximetry and analysis of sweat and other skin secretionsof the subject (e.g., for hormones that may contain information relevantfor the assessment and manipulation of circadian rhythms and sleeppatterns), and/or measuring sleep onset time and duration, and othermeasurements of motion and sleep readily apparent to a person ofordinary skill in the art. The system 100 can use this information toimprove the formulation in real time. The sensors 114 may be separatefrom the control unit 104, however in some embodiments the control unit104 may have components that act as one or more sensor 114. In certainembodiments, sensors 114 include or comprise patches that are worn onthe skin of one or more subjects 118 and related components fordetermining and/or estimating and tracking subjects' 118 consciousnesspatterns (wake/sleep patterns) and circadian state, and other datarelated to shifting and/or aligning the subject's circadian state toexternal schedules based on measured data and smart algorithms. Incertain embodiments, sensors 114 may include or comprise acommunications interface, wired or wireless, that allows for data to betransferred from the sensors 114 to the control unit 104, a computer,tablet or phone, or other device incorporating a real-time clock capableof providing timestamps for the measurements from sensors 114.

The physical layout of system 100 components also can vary withoutconsequence to the system's 100 operation. In one alternativeembodiment, the control unit 104 is physically separated from theolfactory dispensing unit 102 that stores and dispenses the olfactoryagents 120. In such an embodiment, more than one olfactory dispensingunit 102 can be controlled by one control unit 104. The olfactorydispensing units 102 are connected to the control unit 104 via wired orwireless technologies, including Bluetooth, Bluetooth low energy (BLE),Zigbee, Wi-Fi, infrared, near field communication, etc. Referring toFIG. 13 , the system is configured to use wireless electroniccommunication. The control unit 104 provides a user interface 116wherein the users can modify the system's 100 parameters, tweakformulations, etc. This interface can be provided via wirelesstechnologies (Bluetooth, Bluetooth low energy (BLE), Zigbee, Wi-Fi,infrared, near field communication, etc.) or via a display and buttonson the control unit itself. The control unit 104 can be a dedicatedhardware device, built solely for the purpose of controlling thissystem, or a general purpose device, such as a smart-phone or a tabletcomputer running dedicated software that controls the system 100. Thecontrol unit 104 can contain a wireless communication unit 126 thatallows the control unit 104 to communicate electronically using wirelesstechnologies, including the use of devices including wireless routers128 that enable the control unit 104 to remotely communicate with theolfactory dispensing units 102 and sensors 114 to send commands andreceive data.

In an alternate embodiment, the control unit 104, and olfactorydispensing unit 102 with container 122 and actuator 124 reside in thesame physical device. FIG. 14 illustrates an embodiment of the systemwherein the control unit 104 and olfactory dispensing unit 102 operatewithin a single device. The formulation is stored in the control unit's104 memory 108, and the control unit 102 then controls the dispensing ofolfactory agents 120 as required.

FIG. 15 depicts an alternative embodiment of the system wherein thecontrol unit and dispensing unit operate as components of a smart plug.In accordance with an alternative example embodiment of the presentinvention, this smart device can be used to improve the sleep of babiesand infants, by providing olfactory cues circa bedtime. In its simplestform, this alternative embodiment comprises a single physical unit,similar in form to a Glade® Plug-In® device, but rather than simplycontaining scented oil warming components activated by insertion into anoutlet, the smart plug device contains the control unit 104, theolfactory dispensing unit 102 complete with the one or more actuators124 and 122 one or more containers of olfactory agents 120, and wirelesstransceiver 126 in the same package. The control unit 104 can beaccessed and configured via Bluetooth Low Energy or other similartechnology. Configuration comprises simply of inputting the desiredbedtime, duration and intensity of dispensing, and dimensions of thesubjects' 118 environment 101 which in this embodiment would include orcomprise the baby's bedroom. With this information, the system 100 preodorizes the baby's bedroom with olfactory agents 120 every day atbedtime using the control units 104 ability to perform actions as afunction of time, and thereby pre-conditions the baby to want to sleepat that time.

FIG. 16 depicts an exemplary flowchart showing the method 600 forcarrying out the operation of the system 100 to provide adjustment ofconsciousness patterns and circadian states to one or more subjects 118through the monitoring and use of olfactory agents 120 supplied into theenvironment 101 of the one or more subjects 118. At step 602, a user,who may also be one of the subjects 118, provides the olfactorydispensing unit 102 into the desired environment 101 of the one or moresubjects 118, by performing actions such as, initial set up of theolfactory dispensing unit 102, unpacking the olfactory dispensingunit102 from a kit, and supplying power to the olfactory dispensing unit102 by inserting a power supply such as a battery (rechargeable or not)or inserting the olfactory dispensing unit 102 into an electrical outletfound in the desired environment 101 of the one or more subjects 118.

At step 604, a user (e.g., a subject) activates the control unit, byperforming actions such as, initial set up of the control unit 104,unpacking control unit102 from a kit, supplying power to the controlunit 104 by inserting a power supply 112 such as a battery (rechargeableor not) or connecting the control unit 104 to an electrical outlet, thenpowering on the control unit 104 and actuating the olfactory dispensingunit 102 using a control unit 104, and storing data in memory 108gathered from one or more sensors 114 using a processor 106, that areactivated by the control unit 104.

At step 606 a, the one or more sensors 114 may be used to perform one ormore of several functions that use data gathered from the sensors 114and the control unit 104 including: estimating tracking and predicting606 b activity and inactivity data for one or more subjects 118,collecting and monitoring 606 c consciousness patterns data for one ormore subjects 118, and quantifying measurements of circadian outcomes606 d for one or more subjects 118.

At step 608, the user inputs control commands using the user interface116, which use the control unit 104 to actuate the olfactory dispensingunit 102 to dispense the olfactory agents 120 into the environment 101of the one or more subjects 118, according to a specific formulation andparameters selected by the user and stored in the memory 108 of thecontrol unit 104 which performs functions related thereto using theprocessor 106.

At step 610, the control unit 104 and the olfactory dispensing unitelectronically communicate with each other to control further actuationand dispensing of olfactory agents 120 to follow the formulationrequired by the control unit 104. The control unit and the userinterface electronically communicate to provide the user withinformation related to the dispensing of olfactory agents 120 and datarelated to the environment 101 and the one or more subjects 118collected from the sensors 114 or stored in the control unit 104 memory108.

At step 612, the control unit 104 continues to follow the specificformulation as a function of time, actuating the olfactory dispensingunit to continue dispensing various amounts of the olfactory agents 102,thereby modulating sleep/wake and/or a circadian phase of the one ormore subjects 118, based on data related to the environment 101 and theone or more subjects 118 collected from the sensors 114 or stored in thecontrol unit 104 memory 108, where adjustments to timing and amount ofolfactory agents 120 dispensed are made in response to a condition ofthe one or more subjects 118 and an environment 101 of the one or moresubjects 118 as measured by the sensors 114 in real time. This processof adjusted dispensing of olfactory agents 120 based on sensor 114measurements is iteratively repeated to continually adjust the stimulusprovided to the subjects 118, modulating a circadian phase of the one ormore subjects 118 for the duration specified by the control unit 104.The control unit 104 may end dispensing of olfactory agents 120 orintroduce other olfactory agents 120 to signal the end of a particularadministration, consciousness pattern, or circadian phase of the one ormore subjects 118, for example when the sleeping period has ended.

EXAMPLES Example 1: Modulating Circadian Phase

The devices, patches, systems and methods disclosed herein modulate thecircadian phase and/or sleep/wake of a subject in response to thesubject's environment. Such devices, patches, systems and methodsinclude or comprise a step of determining the subject's activity countswhen the subject is awake or asleep. Based on the subject's pattern ofsleep/wake the beginning and end of biological night would then bedetermined. This estimate of early biological night and late biologicalnight allows for the administration of one or more interventions, forexample by controlling or administering light, stimuli and/or agents,capable of shifting the subject's circadian system. For example,melatonin can be administered to a subject in the early biological nightto advance the subject's circadian rhythms and very late biologicalnight to delay the subject's circadian rhythms. Similarly, light can beused in the early biological night to delay phase and late biologicalnight to advance the subject's circadian phase. The particularintervention is determined based on estimated circadian phase during thebiological night/day and desired time of performance. For example, if asubject has one week to phase advance to European time from New York,USA time, the devices, patches and systems disclosed herein would usethe current sleep/wake schedule of that subject to determine when latebiological night is and administer a specific light recipe (e.g., asdescribed in U.S. Provisional Application No. 62/511,692, entitled“Smart light system for circadian system stabilization and conditioningfor mission-critical applications,” and/or International PublicationNumber WO 2018/218241, entitled “Lighting System for Circadian Controland Enhanced Performance,” the entire contents of which are incorporatedby reference herein) during that time and then administer melatonin tothe subject during the early biological night. Similarly, in certainaspects, the devices, patches and systems disclosed herein canadminister, for example, caffeine to a subject in advance of criticalperformance times.

Example 2: 28-Hours Forced Desynchrony Laboratory Results

Through significant experimentation, the inventors were able tosuccessfully collect data during a 28-hours forced desynchronylaboratory study (FD). Activity/inactivity data across seven earth daysare presented in FIG. 8 . These data are from a healthy adolescent-agedparticipant. The graph on the top presents raw actigraphy data collectedby a patch (“Actigpatch”) that shows activity level on the y-axis andearth day on the x-axis. A clear pattern of high activity (wake) and lowactivity (sleep) are seen across study days. The graphs in the middle ofthe figure show sleep/wake estimates based on the raw data in the topgraph. Actigpatch sleep/wake estimates (left), Ambulatory Monitoring,Inc. (AMI) actigraphy sleep/wake estimates (right) and the comparison ofActigpatch to AMI estimates are displayed on the bottom graph. Thesefigures confirm high reliability in sleep/wake estimates betweenActigpatch and AMI devices.

Example 3: Overnight Laboratory Results

Through significant experimentation, the inventors were able tosuccessfully collect data during a one night in-laboratory studymeasuring polysomnography (PSG) and activity/inactivity using theActigpatch. Data are from a healthy 32 year old male. Patch-basedsleep/wake estimates across one night are presented in the graph on thetop of FIG. 9 . The graph in the middle of that figure showspolysomnographically (PSG) measured sleep/wake scored for the samesubject and study according to Rechtschaffen and Kales (1968) criteria,and Actigpatch vs. PSG sleep/wake are compared in the graph at thebottom of FIG. 9 . These data show reliability in sleep/wake estimatesbetween Actigpatch and PSG (a “gold standard” by which sleep/wakepatterns are measured).

Example 4: Circadian Phase Laboratory Results

Through significant experimentation, the inventors were able tosuccessfully collect data presented in FIG. 10 that originates from thefirst in-laboratory night. These data are from a healthy adolescent.Activity level (y-axis) is plotted across 24 hours (1 minute epochs;x-axis). Circadian phase was measured from salivary dim light melatoninonset (DLMO; a “gold standard” by which circadian phases are measured).The first vertical indicator line shows measured circadian phase and thesecond vertical indicator line shows sleep onset. A predictable timeinterval occurs between DLMO and sleep onset and this figuredemonstrates that DLMO (circadian phase) can be estimated from sleepestimates using data collected from patches.

As used herein, a “subject” means a human or animal whose circadianstate (e.g., sleep onset) is modulated by the inventions disclosedherein. In certain embodiments, the subject is also the user of theinventions disclosed herein. Conversely, in other embodiments, thesubject is not the user, but rather the user may be, for example, anadministrative user of the system that is responsible for modulating thecircadian states of one or more subjects (e.g., a group of militarysubjects under the command of the users). In certain embodiments, thesubject is a mammal (e.g., a primate or a human). The subject may be aninfant, a toddler, a child, a young adult, an adult or a geriatric. Incertain aspects, the subject is a member of the military.

As used herein, the term “agent” broadly refers to any compound ormolecule (e.g., a small molecule organic compound) that is delivered toa subject in accordance with the inventions disclosed herein. In certainaspects, the agents modulate circadian biology of the subject. Incertain aspects, the agents are used to modulate a subject's circadianbiology or circadian rhythm (e.g., to align such subject's circadianbiology or rhythm to an external environment). In certain embodiments,the agents include or comprise one or more central nervous systemstimulants (e.g., modafinil, methylphenidate, and/or methylxanthinessuch as caffeine). In certain embodiments, the agents include orcomprise one or more central nervous system depressants (e.g.,melatonin, opioids, hypnotics, benzodiazepines, barbiturate and/orantihistamines). In some aspects, the agent includes modafinil. In someaspects, the agent includes one or more sedatives (e.g., sleeping pills,pain medications and combinations thereof). In some embodiments, theagent includes a circadian phase shifting agent (e.g., melatonin,hormones, light, and combinations thereof). In still other embodiments,the agents include or comprise one or more hormones. In certainembodiments, the agents are topically administered. In certainembodiments, the agents are absorbed transdermally.

As used herein, the terms “modulating” or “modulation” mean to affect,alter or otherwise adjust the circadian biology or circadian phase of asubject. In certain contexts, modulating the circadian biology orcircadian phase of a subject means to correct, adjust or otherwisechange the subject's circadian biology or circadian phase consistentwith such subject's current or anticipated environment. For example,modulating a subject's circadian phase to better coincide or align witha subject's anticipated travel to a new time zone.

As used herein, references to a subject's “circadian phase,” “circadianrhythm” or “circadian biology” generally refer to such subject'sinternal timing of the circadian clock and outputs of the circadianclock housed in the mammalian suprachiasmatic nucleus of the anteriorhypothalamus. For example, the devices, patches, systems and methodsdisclosed herein may, in certain aspects, collect data from a subjectand/or the subject's environment, and use such data to inform the degreeto which such subject's circadian phase will be modulated, shifted orotherwise corrected in accordance with the present inventions.

While certain compositions, devices and methods of the present inventionhave been described with specificity in accordance with certainembodiments, the following examples serve only to illustrate the methodsand compositions of the invention and are not intended to limit thesame.

The articles “a” and “an” as used herein in the specification and in theclaims, unless clearly indicated to the contrary, should be understoodto include or comprise the plural referents. Claims or descriptions thatinclude or comprise “or” between one or more members of a group areconsidered satisfied if one, more than one, or all of the group membersare present in, employed in, or otherwise relevant to a given product orprocess unless indicated to the contrary or otherwise evident from thecontext. The invention includes embodiments in which exactly one memberof the group is present in, employed in, or otherwise relevant to agiven product or process. The invention also includes embodiments inwhich more than one or the entire group members are present in, employedin or otherwise relevant to a given product or process. Furthermore, itis to be understood that the invention encompasses all variations,combinations, and permutations in which one or more limitations,elements, clauses, descriptive terms, etc., from one or more of thelisted claims is introduced into another claim dependent on the samebase claim (or, as relevant, any other claim) unless otherwise indicatedor unless it would be evident to one of ordinary skill in the art that acontradiction or inconsistency would arise. Where elements are presentedas lists, (e.g., in Markush group or similar format) it is to beunderstood that each subgroup of the elements is also disclosed, and anyelement(s) can be removed from the group. It should be understood that,in general, where the invention, or aspects of the invention, is/arereferred to as comprising particular elements, features, etc., certainembodiments of the invention or aspects of the invention consist, orconsist essentially of, such elements, features, etc. For purposes ofsimplicity those embodiments have not in every case been specificallyset forth in so many words herein. It should also be understood that anyembodiment or aspect of the invention can be explicitly excluded fromthe claims, regardless of whether the specific exclusion is recited inthe specification. The publications and other reference materialsreferenced herein to describe the background of the invention and toprovide additional detail regarding its practice are hereby incorporatedby reference.

1-47. (canceled)
 48. A method for adjusting consciousness patterns andcircadian states of one or more subjects, the method comprising:providing an olfactory dispensing unit; actuating the olfactorydispensing unit using a control unit, and storing data from one or moresensors; performing, using the one or more sensors, a function selectedfrom the group consisting of estimating and tracking activity andinactivity data for one or more subjects, collecting and monitoringconsciousness patterns data for one or more subjects, and quantifyingmeasurements of circadian outcomes for one or more subjects; inputting,using a user interface, control commands for using the control unit toactuate the olfactory dispensing unit to dispense the olfactory agents;electronically communicating, between the olfactory dispensing unit andthe control unit and between the user interface and control unit; anddispensing of the olfactory agents, thereby modulating a circadian phaseof the one or more subjects in response to a condition of the one ormore subjects and an environment of the one or more subjects.
 49. Themethod of claim 48, wherein the one or more sensors are configured tocollect and monitor consciousness patterns data of the one or moresubjects; wherein the consciousness patterns comprise the subjects'sleep/wake patterns; wherein the monitoring consciousness patterns datacomprises using the one or more sensors to quantify the sleep andcircadian system of the one or more subjects by sensing at least onesignal selected from the group consisting of rest and activity cyclesusing actigraphy, signals using polysomnography, skin temperature, sleeponset time and duration, environmental light exposure, total lightdosage received by the one or more subjects over a period of time, pulseoximetry, blood oxygen saturation levels, sweat and other skinsecretions of the one or more subjects, and biofeedback signalsindicative of sleep patterns of the one or more subjects; and whereinthe control unit uses consciousness patterns data of each of the onemore subjects to optimize a formulation of the olfactory agents inreal-time to provide cues to achieve a stimuli response in each of theone or more subjects, wherein the stimuli response comprises one or moreactions selected from the group consisting of shifting of timing ofsleep, reducing sleep onset latency, enhancing sleep consolidation andreducing variability in sleep patterns.
 50. The method of claim 48,wherein the control unit actuates the olfactory dispensing unit as afunction of time, according to a formulation, using a timing deviceconfigured to keep time, memory to store the formulation and data fromthe one or more sensors and other system components, using a processorto compute relevant parameters and adjust the formulation in real-timeto control timing when the olfactory agents are dispensed and amountsindicating a quantity of the olfactory agents to dispense, wherein theolfactory dispensing unit is configured to dispense the olfactory agentsusing an actuator that uses at least one mechanism selected from thegroup consisting of electrical heating of olfactory agents comprisingone or more liquids actuated by the control unit at specific timesdesignated by the formulation to cause evaporation, ultrasonicnebulizers comprising a vibrating transducer actuated by the controlunit, air-stream atomizers comprising an air-stream generator actuatedby the control unit, and volatile substances stored in a container thatis opened and closed by the control unit to respectively allow andprevent vapors of the olfactory agents to propagate out of the olfactorydispensing unit and into the environment of the one or more subjects.51. The system of claim 48, wherein the olfactory agents comprise one ormore agents selected from the group consisting of central nervous systemdepressants and a central nervous system stimulators.
 52. A system foradjusting consciousness patterns and circadian states of one or moresubjects, the system comprising: an olfactory dispensing unit configuredto dispense olfactory agents; a control unit configured to actuate theolfactory dispensing unit and store data from one or more sensorsconfigured to perform one or more functions selected from the groupconsisting of estimating and tracking activity and inactivity data forthe one or more subjects, collecting and monitoring consciousnesspatterns data for the one or more subjects, and quantifying measurementsof circadian outcomes for the one or more subjects; a user interfaceoperative to receive control commands, input from a user, for using thecontrol unit to actuate the olfactory dispensing unit to dispense theolfactory agents; wherein the olfactory dispensing unit and the controlunit are configured to be in electronic communication and wherein theuser interface and the control unit are configured to be in electroniccommunication; and wherein dispensing of the olfactory agents modulatesa circadian phase and consciousness state of the one or more subjects inresponse to a condition of the one or more subjects and an environmentof the one or more subjects.
 53. The system of claim 52, wherein theolfactory dispensing unit comprises one or more containers that storethe olfactory agents, and one or more actuators that dispense theolfactory agents into the environment of the one or more subjects. 54.The system of claim 52, wherein the control unit actuates the olfactorydispensing unit as a function of time, according to a formulation, usinga timing device configured to keep time, memory to store the formulationand data from the one or more sensors and other system components, usinga processor to compute relevant parameters and adjust the formulation inreal-time to control timing when olfactory agents are dispensed andamounts indicating how much olfactory agents are dispensed, wherein theolfactory dispensing unit is configured to dispense olfactory agentsusing an actuator that uses at least one mechanism selected from thegroup consisting of electrical heating of olfactory agents comprisingone or more liquids actuated by the control unit at specific timesdesignated by the formulation to cause evaporation, ultrasonicnebulizers comprising a vibrating transducer actuated by the controlunit, one or more solids in contact with a heating element actuated bythe control unit at specific times designated by the formulation todelivery of olfactory agents, ultrasonic nebulizers comprising avibrating transducer actuated by the control unit, air-stream atomizerscomprising an air-stream generator actuated by the control unit, andvolatile substances stored in a container that is opened and closed bythe control unit to allow and prevent vapors of the olfactory agents topropagate out of the olfactory dispensing unit into the environment ofthe one or more subjects.
 55. The system of claim 52, wherein theconsciousness patterns comprise the subjects' sleep/wake patterns; andwherein the olfactory agents modulate sleep/wake patterns of the one ormore subjects.
 56. The system of claim 52, wherein the one or moresensors are configured to perform collecting and monitoring ofconsciousness patterns data for the one or more subjects, wherein themonitoring consciousness patterns data comprises using the sensors toquantify the sleep and circadian system of the one or more subjects bysensing at least one signal selected from the group consisting of restand activity cycles using actigraphy, signals using polysomnography,skin temperature, sleep onset time and duration, environmental lightexposure, total light dosage received by the one or more subjects over aperiod of time, pulse oximetry, blood oxygen saturation levels, sweatand other skin secretions of the one or more subjects, and biofeedbacksignals indicative of sleep patterns of the one or more subjects. 57.The system of claim 56, wherein the control unit uses consciousnesspatterns data of each of the one more subjects to optimize a formulationof the olfactory agents in real-time to provide cues to achieve astimuli response in each of the one or more subjects, wherein thestimuli response comprises one or more actions selected from the groupconsisting of shifting of timing of sleep, adjusting circadian phase,enhancing alertness, enhancing performance, reducing sleep onsetlatency, enhancing sleep consolidation and reducing variability in sleeppatterns and adjusting mood.
 58. The system of claim 52, furthercomprising at least one smart olfactory dispensing unit and softwarethat tracks sleep history information of the one or more subjects, thensets a sleep-and-wake schedule for the one or more subjects anddesignates specific olfactory agents assigned to activity eventsselected from the group consisting of bedtime, risetime, nap time, awaketime and combinations thereof, wherein the olfactory agents will beautomatically dispensed at specific times of day to facilitate at leastone action selected from the group consisting of sleep, wake, increasedenergy, and relaxation, wherein the system uses algorithms to avoidhabituation to olfactory agents relative to onset of activity events.59. The system of claim 52, wherein the one or more sensors areconfigured to sense the environment of the one or more subjects bydirectly measuring the concentration of olfactory agents in air of theenvironment of the one or more subjects allowing the system to control aquantity of olfactory agents present in the environment of the one ormore subjects and wherein the one or more sensors comprise a sensorselected from the group consisting of sensors configured for estimatingconcentrations in air for certain specific gases, sensors configured forestimating concentrations in air for volatile organic compounds, sensorsthat map aromas to images and combinations thereof.
 60. The system ofclaim 52, wherein a formulation comprises a list of times and desiredconcentrations of the olfactory agents at each time, wherein theconcentrations of olfactory agents for use the formulation aredetermined from measured amounts of the olfactory agents absorbed by theone or more subjects over a certain exposure period, and whereinconcentrations of olfactory agents for use in the formulation aremeasured using absolute units, empirical units and combinations thereof.61. The system of claim 52, wherein the control unit actuates theolfactory dispensing unit to dispense olfactory agents with output andintensity based upon measurements of circadian outcomes and applicationof machine learning techniques to indirectly infer adequateconcentrations of a formulation and the olfactory agents in anenvironment of the one or more subjects.
 62. The system of claim 52,wherein the olfactory dispensing unit and the control unit are bothcontained within a physical device that further comprises a smart plugand wireless communication unit, and wherein a formulation is stored inmemory of the control unit controlling dispensing of the olfactoryagents and the control unit is controlled remotely using wirelesselectronic communication sent from a separate device comprising the userinterface configured to receive input from the user to modify parametersof the system and adjust the formulations.
 63. The system of claim 52,wherein the control unit is physically separated from the olfactorydispensing unit and communicates electronically with the olfactorydispensing unit using wired or wireless technologies, wherein thecontrol unit uses processors, memory and dedicated software that controlthe system and the control unit is physically connected to the userinterface configured to receive input from the user to modify parametersof the system and adjust the formulations.
 64. The system of claim 52,wherein the control unit, the olfactory dispensing unit and the one ormore sensors communicate electronically using transceivers, wirelesscommunication units and wireless routers configured to operate usingwireless technology standards selected from the group consisting ofBluetooth, Bluetooth low energy (BLE), Zigbee, Wi-Fi, infrared, nearfield communication and combinations thereof.
 65. The system of claim52, further comprising a fan, configured to circulate air through thesystem.
 66. The system of claim 52, wherein the olfactory agentscomprise one or more agents selected from the group consisting ofcentral nervous system depressants and a central nervous systemstimulators.
 67. The system of claim 52, wherein one or more subjectsare human.